Broad neutralization against SARS-CoV-2 variants induced by a modified B.1.351 protein-based COVID-19 vaccine candidate (preprint)

Beginning in late 2020, the emergence and spread of multiple variant SARS-CoV-2 strains harboring mutations which may enable immune escape necessitates the rapid evaluation of second generation COVID-19 vaccines, with the goal of inducing optimized immune responses that are broadly protective. Here we demonstrate in a mouse immunogenicity study that two doses of a modified B.1.351 spike (S)-Trimer vaccine (B.1.351 S-Trimer) candidate can induce strong humoral immune responses that can broadly neutralize both the original SARS-CoV-2 strain (Wuhan-Hu-1) and Variants of Concern (VOCs), including the UK variant (B.1.1.7), South African variant (B.1.351) and Brazil variant (P.1). Furthermore, while immunization with two doses (prime-boost) of Prototype S-Trimer vaccine (based on the original SARS-CoV-2 strain) induced lower levels of cross-reactive neutralization against the B.1.351 variant, a third dose (booster) administered with either Prototype S-Trimer or B.1.351 S-Trimer was able to increase neutralizing antibody titers against B.1.351 to levels comparable to neutralizing antibody titers against the original strain elicited by two doses of Prototype S-Trimer.

Human Identical Sequences of SARS-CoV-2 Promote Clinical Progression of COVID-19 by Upregulating Hyaluronan via NamiRNA-Enhancer Network (preprint)

The COVID-19 pandemic is a widespread and deadly public health crisis. The pathogen SARS-CoV-2 replicates in the lower respiratory tract and causes fatal pneumonia. Although tremendous efforts have been put into investigating the pathogeny of SARS-CoV-2, the underlying mechanism of how SARS-CoV-2 interacts with its host is largely unexplored. Here, by comparing the genomic sequences of SARS-CoV-2 and human, we identified five fully conserved elements in SARS-CoV-2 genome, which were termed as "human identical sequences (HIS)". HIS are also recognized in both SARS-CoV and MERS-CoV genome. Meanwhile, HIS-SARS-CoV-2 are highly conserved in the primate. Mechanically, HIS-SARS-CoV-2 RNA directly binds to the targeted loci in human genome and further interacts with host enhancers to activate the expression of adjacent and distant genes, including cytokines gene and angiotensin converting enzyme II (ACE2), a well-known cell entry receptor of SARS-CoV-2, and hyaluronan synthase 2 (HAS2), which further increases hyaluronan formation. Noteworthily, hyaluronan level in plasma of COVID-19 patients is tightly correlated with severity and high risk for acute respiratory distress syndrome (ARDS) and may act as a predictor for the progression of COVID-19. HIS antagomirs, which downregulate hyaluronan level effectively, and 4-Methylumbelliferone (MU), an inhibitor of hyaluronan synthesis, are potential drugs to relieve the ARDS related ground-glass pattern in lung for COVID-19 treatment. Our results revealed that unprecedented HIS elements of SARS-CoV-2 contribute to the cytokine storm and ARDS in COVID-19 patients. Thus, blocking HIS-involved activating processes or hyaluronan synthesis directly by 4-MU may be effective strategies to alleviate COVID-19 progression.

S-Trimer, a COVID-19 subunit vaccine candidate, induces protective immunity in nonhuman primates (preprint)

SARS-CoV-2 is the underlying cause for the COVID-19 pandemic. Like most enveloped RNA viruses, SARS-CoV-2 uses a homotrimeric surface antigen to gain entry into host cells. Here we describe S-Trimer, a native-like trimeric subunit vaccine candidate for COVID-19 based on Trimer-Tag technology. Immunization of S-Trimer with either AS03 (oil-in-water emulsion) or CpG 1018 (TLR9 agonist) plus alum adjuvants induced high-levels of neutralizing antibodies and Th1-biased cellular immune responses in animal models. Moreover, rhesus macaques immunized with adjuvanted S-Trimer were protected from SARS-CoV-2 challenge compared to vehicle controls, based on clinical observations and reduction of viral loads in lungs. Trimer-Tag may be an important new platform technology for scalable production and rapid development of safe and effective subunit vaccines against current and future emerging RNA viruses.

Cryo-EM structure of S-Trimer, a subunit vaccine candidate for COVID-19 (preprint)

Less than a year after its emergence, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 22 million people worldwide with a death toll approaching 1 million. Vaccination remains the best hope to ultimately put this pandemic to an end. Here, using Trimer-Tag technology, we produced both wild-type (WT) and furin site mutant (MT) S-Trimers for COVID-19 vaccine studies. Cryo-EM structures of the WT and MT S-Trimers, determined at 3.2 Angstrom and 2.6 Angstrom respectively, revealed that both antigens adopt a tightly closed conformation and their structures are essentially identical to that of the previously solved full-length WT S protein in detergent. These results validate Trimer-Tag as a platform technology in production of metastable WT S-Trimer as a candidate for COVID-19 subunit vaccine.

Prevalence and clinical features of 2019 novel coronavirus disease (COVID-19) in the Fever Clinic of a teaching hospital in Beijing: a single-center, retrospective study (preprint)

Background With the spread of COVID-19 from Wuhan, Hubei Province to other areas of the country, medical staff in Fever Clinics faced the challenge of identifying suspected cases among patients with respiratory infections manifested with fever. We aimed to describe the prevalence and clinical features of COVID-19 as compared to pneumonias of other etiologies in a Fever Clinic in Beijing. Methods In this single-center, retrospective study, 342 cases of pneumonia were diagnosed in Fever Clinic in Peking University Third Hospital between January 21 to February 15, 2020. From these patients, 88 were reviewed by panel discussion as possible or probable cases of COVID-19, and received 2019-nCoV detection by RT-PCR. COVID-19 was confirmed by positive 2019-nCoV in 19 cases, and by epidemiological, clinical and CT features in 2 cases (the COVID-19 Group, n=21), while the remaining 67 cases served as the non-COVID-19 group. Demographic and epidemiological data, symptoms, laboratory and lung CT findings were collected, and compared between the two groups. Findings The prevalence of COVID-19 in all pneumonia patients during the study period was 6.14% (21/342). Compared with the non-COVID-19 group, more patients with COVID-19 had an identified epidemiological history (90.5% versus 32.8%, P<0.001). The COVID-19 group had lower WBC [5.19x10^9/L ({+/-}1.47) versus 7.21x10^9/L ({+/-}2.94), P<0.001] and neutrophil counts [3.39x10^9/L ({+/-}1.48) versus 5.38x10^9/L ({+/-}2.85), P<0.001] in peripheral blood. However, the percentage and count of lymphocytes were not different. On lung CT scans, involvement of 4 or more lobes was more common in the COVID-19 group (45% versus 16.4%, P=0.008). Interpretation In the period of COVID-19 epidemic outside Hubei Province, the prevalence of COVID-19 in patients with pneumonia visiting to our Fever Clinic in Beijing was 6.14%. Epidemiological evidence was important for prompt case finding, and lower blood WBC and neutrophil counts may be useful for differentiation from pneumonia of other etiologies.

Reflections on Reducing Pathogens in Sludge in the Case of COVID-19 Epidemic

Based on the problem that the novel coronavirus (SARS-CoV-2) can enter the urban drainage system through the excretion of patients' faces into the sewer, the fate of infective viruses in the urban water cycle was analyzed. Then, it was concluded that attention should be paid to the risk of virus spreading through sludge after the virus enters the urban drainage system. In the case of COVID-19 epidemic, it is impartant to summarize and reflect on the pathogen control during sludge treatment and disposal process in China. Therefore, the relevant standards and policies of sludge sterilization and disinfection in China have been systematically combed, and the relevant research results of the United States and the European Union have been studied. It has been considered that the sludge is a good carrier of pathogens;the standard restrictions on pathogens in sludge in our country are relatively loose currently. So it is necessary to strengthen the experiments and research on inactivation of pathogens in sludge, and to formulate the index and limit value of pathogens. The SARS-CoV-2 is an enveloped virus that can be relatively easily killed by antivirus agent. Therefore, adding disinfectant to the sludge pretreatment section is an effective measure to control pathogens during the epidemic. Aerobic fermentation, anaerobic digestion, lime stabilization, thermal drying, and radiation treatment can effectively reduce pathogens. During the epidemic period, sludge disposal methods are recommended to adopt incineration or co-incineration. For areas where the harmless disposal capacity of sludge is insufficient, the implementation of compliance sludge disposal outlet should be promoted. In addition, in order to reduce the exposure risk, in the sludge treatment and disposal process, the better sealing device should be preferred.